Highly functionalized pyrrolidine based arginase inhibitors have been described in U.S. Patent Publication No. 2017/0121352. For instance, U.S. Patent Publication No. 2017/0121352 describes the synthesis of potent arginase inhibitors such as (3R,4S)-1-(L-alanyl)-3-amino-4-(3-boronopropyl)pyrrolidine-3-carboxylic acid. These ring-constrained arginase inhibitors have tremendous potential as novel therapeutics for a wide variety of diverse diseases such as cancer, asthma, cystic fibrosis, myocardial reperfusion injury, sickle cell anemia, erectile dysfunction, and leishmaniasis. A description of the role of arginase in these diseases can be found in numerous papers, review articles and patents, including U.S. Pat. No. 9,200,011 (Ring constrained analogs as arginase inhibitors), Trends Pharmacol. Sci. 2015, 36(6): 395-405 (“Arginase: an old enzyme with new tricks”), and Clinical and Experimental Immunology 2012, 167: 195-205 (“Immunology in the clinic review series; focus on cancer: tumor-associated macrophages: undisputed stars of the inflammatory tumor microenvironment”).
Although these ring-constrained arginase inhibitors have tremendous potential as new treatments for various diseases, they contain multiple chiral centers making them inherently complex and challenging to prepare on a commercial scale. Improved methods for making such compounds would be advantageous.